1. Field of the Invention
The present invention relates to micronized particles of a low-dosage strength active ingredient for dry powder formulations for inhalation and methods for preparing them. In particular the present invention relates to micronized particles of low-dosage strength active ingredients which can homogeneously and easily disperse in a dry powder formulation to be administered by means of a dry powder inhaler device. The present invention also relates to formulations of such micronized particles in the form of powders for inhalation.
2. Discussion of the Background
The administration of pharmacologically active ingredients by inhalation to the airways is a widely used technique especially for the treatment of reversible airway obstruction, inflammation, and hyperresponsiveness.
This technique is also used for the administration of active agents having systemic action, which are absorbed via the lungs, into the bloodstream. Some of the most widely used systems for the administration of drugs to the airways are the dry powder inhalers (DPIs). Drugs intended for inhalation as dry powders by means of DPIs should be used in the form of particles of few microns (μm) particle size.
Micronized particles generally considered “respirable” are those with a particle size comprised from 0.5 to 10 microns, preferably 0.5 to 5 microns, as they are capable of penetrating into the lower airways, i.e. the bronchiolar and alveolar sites, which are the site of action for the pulmonary drugs and where absorption takes place for the systemic drugs. Larger particles are mostly deposited in the oropharyngeal cavity so they cannot reach said sites, whereas the smaller ones are exhaled.
The desirable particle sizes are generally achieved by grinding or so-called micronization of the active agent.
In the prior art, several documents deal with the physico-chemical characteristics of micronized active ingredients for inhalation in particular in terms of particle size (see, US 2004/002510, WO 03/90715, WO 03/24396, WO 02/85326, WO 98/52544, EP 680752, WO 98/17676, and WO 95/01324).
Although micronization of the drug is essential for deposition into the lower respiratory tract during inhalation, it is known that the finer the particles are, the stronger are the cohesion forces that favour the formation of agglomerates.
For this reason, powders for inhalation have been commonly formulated by mixing the micronized drug with a carrier (generally, a physiologically acceptable material, commonly lactose or mannitol, preferably α-lactose monohydrate) consisting of coarser particles to give rise to the so-called “interactive ordered mixtures”.
However, the present inventors have verified that agglomerates formation may also occur during the preparation of the “interactive ordered mixtures” i.e. during the blending of the active ingredient fine particles with the coarser excipient particles. The formation of agglomerates among the fine particles of the active ingredient jeopardizes their dispersion onto the surface of the coarse excipient particles and hence it is detrimental to the possibility of achieving a good uniformity of distribution of the active ingredient in the powder mixture and hence a good accuracy of the dose. The formation of agglomerates is particularly critical when a low-dosage strength active ingredient is used, e.g. an active ingredient endowed with particularly high potency which is present in the powder formulation in a very low concentration.
In fact, the lower the active ingredient weight percent concentration based on the total weight of the formulation is, the higher is the detrimental effect of the agglomerates on the uniformity of the active ingredient in the powder blend. The lack of homogeneity of the powder, due to the formation of agglomerates, involves the risk of an over or under dosage. Thus, the agglomeration phenomenon, together with other properties such as high adhesiveness degree, leads to problems in the manufacturing of a powder formulation provided with good dosage reproducibility when administered by DPIs.
WO 2005/089717 discloses avoiding agglomeration by preparing microparticles consisting of a low-dosage strength therapeutically active ingredient and excipient particles with a defined particle size that are obtained by pre-mixing or pre-milling. However the preparation of said microparticles is a time-consuming step. Moreover the present inventors have found that such microparticles can face stability problems after storage of the final formulation.
Thus there remains a need for micronized low-dosage strength active agents to be administered by inhalation with a DPI device which, when formulated as interactive ordered mixtures, can easily and homogeneously disperse in the formulation giving rise to a good uniformity of distribution of the particles and hence an adequate accuracy of the metered dose, together with a good performance in terms of delivered dose and respirable fraction.